RNA splicing is a highly regulated process dependent on sequences near splice sites. Insertions of Alu retrotransposons can disrupt splice sites or bind splicing regulators. We hypothesized that some common inherited polymorphic Alu insertions are responsible for splicing QTLs (sQTL). We focused on intronic Alu variants mapping within 100 bp of an alternatively used exon and screened for those that alter splicing. We identify five loci, 21.7% of those assayed, where the polymorphic Alu alters splicing. While in most cases the Alu promotes exon skipping, at one locus the Alu increases exon inclusion. Of particular interest is an Alu polymorphism in the CD58 gene. Reduced CD58 expression is associated with risk for developing multiple sclerosis. We show that the Alu insertion promotes skipping of CD58 exon 3 and results in a frameshifted transcript, indicating that the Alu may be the causative variant for increased MS risk at this locus. Using RT-PCR analysis at the endogenous locus, we confirm that the Alu variant is a sQTL for CD58. In summary, altered splicing efficiency is a common functional consequence of Alu polymorphisms including at least one instance where the variant is implicated in disease risk. This work broadens our understanding of splicing regulatory sequences around exons.
Alu elements are the most abundant source of nonallelic homology that influences genetic instability in the human genome. When there is a DNA double-stranded break, the Alu element's high copy number, moderate length and distance and mismatch between elements uniquely influence recombination processes. We utilize a reporter-gene assay to show the complex influence of Alu mismatches on Alurelated repeat-mediated deletions (RMDs). The Alu/Alu heteroduplex intermediate can result in a nonallelic homologous recombination (HR). Alternatively, the heteroduplex can result in various DNA breaks around the Alu elements caused by competing nucleases. These breaks can undergo Alt-nonhomologous end joining to cause deletions focused around the Alu elements. Formation of these heteroduplex intermediates is largely RAD52 dependent. Cells with low ERCC1 levels utilize more of these alternatives resolutions, while cells with MSH2 defects tend to have more RMDs with a specific increase in the HR events. Therefore, Alu elements are expected to create different forms of deletions in various cancers depending on a number of these DNA repair defects.
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